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Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency
Author(s) -
Murray Jennie E.,
Bicknell Louise S.,
Yigit Gökhan,
Duker Angela L.,
Kogelenberg Margriet,
Haghayegh Sara,
Wieczorek Dagmar,
Kayserili Hülya,
Albert Michael H.,
Wise Carol A.,
Brandon January,
Kleefstra Tjitske,
Warris Adilia,
Flier Michiel,
Bamforth J. Steven,
Doonanco Kurston,
Adès Lesley,
Ma Alan,
Field Michael,
Johnson Diana,
Shackley Fiona,
Firth Helen,
Woods C. Geoffrey,
Nürnberg Peter,
Gatti Richard A.,
Hurles Matthew,
Bober Michael B.,
Wollnik Bernd,
Jackson Andrew P.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22461
Subject(s) - failure to thrive , nijmegen breakage syndrome , biology , microcephaly , immunodeficiency , malignancy , bone marrow failure , genetics , immunology , ataxia telangiectasia , dna damage , dna , immune system , stem cell , haematopoiesis
Ligase IV syndrome is a rare differential diagnosis for N ijmegen breakage syndrome owing to a shared predisposition to lympho‐reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG 4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG 4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC −10.1 s.d., height −5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG 4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG 4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.